The Secretory Route of the Leaderless Protein Interleukin 1β Involves Exocytosis of Endolysosome-related Vesicles

TLDR

IL‑1β is a secretory protein that lacks a signal peptide and therefore does not follow the classical endoplasmic reticulum‑to‑Golgi secretion pathway. The study demonstrates that IL‑1β is exported via a leaderless secretory route that relies on regulated exocytosis of preterminal endocytic vesicles. IL‑1β precursor is mainly cytosolic but a subset resides in late‑endosome/lysosome‑like vesicles that co‑express Lamp‑1 and cathepsin D, and its secretion is triggered by acidotropic drugs, ATP, or hypotonic stress while inhibited by glibenclamide, indicating regulated exocytosis of pro‑IL‑1β–containing vesicles.

Abstract

Interleukin 1β (IL-1β), a secretory protein lacking a signal peptide, does not follow the classical endoplasmic reticulum-to-Golgi pathway of secretion. Here we provide the evidence for a “leaderless” secretory route that uses regulated exocytosis of preterminal endocytic vesicles to transport cytosolic IL-1β out of the cell. Indeed, although most of the IL-1β precursor (proIL-1β) localizes in the cytosol of activated human monocytes, a fraction is contained within vesicles that cofractionate with late endosomes and early lysosomes on Percoll density gradients and display ultrastructural features and markers typical of these organelles. The observation of organelles positive for both IL-1β and the endolysosomal hydrolase cathepsin D or for both IL-1β and the lysosomal marker Lamp-1 further suggests that they belong to the preterminal endocytic compartment. In addition, similarly to lysosomal hydrolases, secretion of IL-1β is induced by acidotropic drugs. Treatment of monocytes with the sulfonylurea glibenclamide inhibits both IL-1β secretion and vesicular accumulation, suggesting that this drug prevents the translocation of proIL-1β from the cytosol into the vesicles. A high concentration of extracellular ATP and hypotonic medium increase secretion of IL-1β but deplete the vesicular proIL-1β content, indicating that exocytosis of proIL-1β–containing vesicles is regulated by ATP and osmotic conditions.